Indian J Surg Oncol (March 2016) 7(1):11–17 DOI 10.1007/s13193-015-0442-8
ORIGINAL ARTICLE
Assessment of Tumor Response and Resection Rates in Unresectable Colorectal Liver Metastases Following Neoadjuvant Chemotherapy with Cetuximab S. P. Somashekhar 1 & K. R. Ashwin 2 & Shabber S. Zaveri 3 & Amit Rauthan 4 & Poonam Patil 4
Received: 26 April 2015 / Accepted: 23 June 2015 / Published online: 5 July 2015 # Indian Association of Surgical Oncology 2015
Abstract To investigate efficacy and safety of cetuximab combined with neo adjuvant chemotherapy regimen in patients with unresectable colorectal liver. This was a prospective trial with rate of Ro liver metastases resection as primary end point. Between January 2010 and December 2014, 46 patients with unresectable liver metastases from colon or rectum were enrolled. Patients received Cetuximab along with neoadjuvant chemotherapy where 34 (74 %) and 12 (26 %) patients received FOLFOX and FOLFIRI, respectively. They were assessed for response after 2–3 cycles by CT scan. Patients with resectable disease were offered liver surgery within 3–6 weeks of the last treatment cycle. The primary end point was resection rate of liver metastases, which was evaluated in all patients. Secondary end points were response rate according to Response evaluation criteria in solid tumors
* S. P. Somashekhar [email protected] K. R. Ashwin [email protected]; [email protected] Shabber S. Zaveri [email protected] Amit Rauthan [email protected] Poonam Patil [email protected] 1
Manipal Comprehensive Cancer Center, Business Advisory Board of MHEPL Manipal Hospital, Bangalore 560017, India
2
Manipal Comprehensive Cancer Centre, No 8, second Anjaneya temple street Seshadripurum, Bangalore 560020, India
3
Department of Surgical Oncology, Manipal Comprehensive Cancer Centre, #98 HAL airport road, Bangalore 560017, India
4
Department of Medical Oncology, Manipal Comprehensive Cancer Centre, #98 HAL airport road, Bangalore 560017, India
(RECIST) criteria, perioperative morbidity and mortality. An objective response was observed in 28 (60.9 %) patients. Seven (15.2 %) patients were reported radiologically to have a complete response (CR); 21 (45.7 %) patients had radiological partial response (PR). An additional 12 patients (26.1 %) demonstrated stable disease (SD) and only six patients (13.0 %) had disease progression (PD). Microscopically complete resections (R0 resection) was performed in all 28 patients (60.9 %). The most frequent toxicities were skin rash and diarrhoea. There was no operative mortality. Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. Complete resection of previously unresectable colorectal liver metastases can be performed with minimal morbidity and mortality. This therapeutic strategy involves a multimodal approach. Keywords Cetuximab . mCRR . Indian study . Liver metastases . Colorectal
Introduction Colorectal carcinoma is one of the most common causes of cancer-related mortalities in both India and the world. Almost half the patients with colorectal cancer will eventually develop liver metastases during the natural course of the disease [1]. The liver is a frequent site of colorectal metastases, and 15 to 25 % of patients have liver metastases at diagnosis. In addition, 50 to 60 % of patients with localized disease at diagnosis eventually develop metastatic disease [2]. Historically, the median survival of patients with metastatic colorectal cancer treated with palliative care is approximately 6 to 12 months [3]. Surgical management of hepatic metastases of colorectal cancer has now become standard of treatment. But only a
12
minority of patients (10–15 %) are considered candidates for resection with overall 5-year survival rates ranging between 25 and 40 %. Therefore, most colorectal hepatic metastases (an estimated 70–80 %) on presentation are unresectable [4, 5]. It was first reported in 1996 by Bismuth et al. that preoperative chemotherapy, using oxaliplatin plus 5- fluorouracil (5-FU) and leucovorin [LV], enabled initially unresectable colorectal liver metastasis (CRLM) patients to gain the chance of undergoing liver resection with an improved 5-year OS of 40 % [6]. Neo adjuvant chemotherapy is currently accepted as the way forward for improving survival in patients with initially unresectable CRLM. Standard combination chemotherapy regimens comprising 5- fluorouracil (5-FU) plus leucovorin [LV] in combination with irinotecan, typically FOLFIRI or oxaliplatin (FOLFOX) have been reported to facilitate the resection of 9–40 % of initially unresectable metastases, and a median survival of 15 to 20 months [7–9]. Although, intensified chemotherapy such as FOLFOXIRI (i.e., oxaliplatin, 5-FU/LV and irinotecan) has been shown to have high response and conversion rates (19 %); however, it has not been generally recommended thus far due to its considerable toxicity [10]. For patients with disease progression during preoperative chemotherapy predicts poor prognosis, for which a change to other alternative chemotherapy regimens is recommended [11]. New data emerging from randomized trials suggest that the addition of targeted agents and a third cytotoxic might be even more effective. The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab is effective when used in combination with chemotherapy. It has a clear indication in second- and third-line treatment of metastatic colorectal cancer. It was recently investigated both as monotherapy and in combination with chemotherapy in the first-line setting. The addition of cetuximab to doublet chemotherapy regimens such as FOLFIRI or FOLFOX has been shown to increase response rates (RR), and prolong progression-free survival (PFS) and overall survival (OS) times in the first-line treatment of patients with CRLM and KRAS wild-type tumours. In these trials, the resectability rate for liver metastases was improved by the addition of cetuximab to chemotherapy, when retrospectively evaluated [12, 13]. More patients with CRLM would be rendered resectable with effective preoperative therapy, as the addition of cetuximab to chemotherapy is feasible in first-line therapy, which has been confirmed in a randomized phase II multicentre study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in the neo-adjuvant treatment of nonresectable colorectal liver metastases confined to the liver (the CELIM study), response rates of 85
Indian J Surg Oncol (March 2016) 7(1):11–17
and 66 % were reported in the FOLFOX6 and FOLFIRI arms, respectively [14]. It is concluded that cetuximab when combined with firstline chemotherapy increases the possibility of resection for patients with initially unresectable liver without increasing surgical mortality or liver injury [15]. The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved PFS compared with chemotherapy alone. They confirmed the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC [16, 17]. Cetuximab combined with triple cytotoxic drug therapy is evaluated, for potential extra efficacy on response rates and clinical outcome. Definitive results from the preoperative chemotherapy for hepatic resection (POCHER) study revealed an RR of 79 % and a complete resection rate of 63 % achieved by FOLFOXIRI plus cetuximab [18]. KRAS encodes a small G protein that links liganddependent receptor activation to intracellular pathways of the EGFR signalling cascade. Mutation at key sites within the gene, commonly at codons 12 and 13, causes constitutive activation of KRAS-associated signalling. Evidence indicates that tumour KRAS mutation is associated with the inefficacy of cetuximab [19]. A recent meta-analysis based on the CRYSTAL and OPUS trials reported the updated clinical efficacy of cetuximab combination therapy according to KRAS and BRAF mutation status. This analysis confirmed that in KRAS wild-type patients, the addition of cetuximab in first-line treatment achieves a statistically significant improvement in response rates, progression free survival, and overall survival compared with chemotherapy alone. However, it also concluded that BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab. BRAF is more likely to be a prognostic factor as the clinical outcome in BRAF mutant patients is worse than those with BRAF wildtype tumours in terms of RR, PFS and OS. Thus, BRAF testing is probably not essential when deciding whether cetuximab should be used [20]. The evaluation of tumour response to treatment is critical for managing patients with advanced cancer. Tumour response, partial and complete response, is the most common criterion used to evaluate the effect of treatment. Imaging and, in particular computed tomography (CT) scan is used to monitor chemotherapy according to the new guidelines for response evaluation (RECIST criteria) [21]. Complete response is usually defined as the disappearance of target lesions on imaging and is considered as a good indicator to evaluate the efficacy of chemotherapy. A potential drawback of neoadjuvant chemotherapy in metastatic colorectal cancer patients is missing the optimal timing of liver resection because of
Indian J Surg Oncol (March 2016) 7(1):11–17
complete response of liver tumours during chemotherapy. Studies show that there is a discrepancy between a complete response being seen on imaging and the complete clearance of cancer. Macroscopic residual disease was found during surgical exploration at the site of liver metastases that were considered to have disappeared on imaging. In addition, in patients with no obvious disease at surgery, microscopic cancer was observed in the resected specimen. Therefore, although complete response seen on imaging may be a useful criterion for evaluating the efficacy of chemotherapy, it does not mean the cure of cancer in most cases [22]. The technical problems for the surgeon are to identify the precise site of the liver needed to be resected and to achieve sufficient resection margin, since he cannot see or palpate any tumour or visualize it using intraoperative ultrasound. To avoid such an intractable condition, it is recommended that the evaluation of liver lesions be repeated every 2 months during preoperative chemotherapy and medical oncologists should refer patients to surgeons as soon as liver metastases are resectable before they have completely disappeared. Despite advances in survival with chemotherapy, surgical resection of hepatic metastases is still considered the only curative option for patients with liver metastases. Liver resection should be reconsidered if the tumour shows response after chemotherapy. The current criteria focus on what should be left after hepatic resection. Previous criteria for resection, such as the size, location, number of intrahepatic metastases and the presence of bilobar or extra hepatic disease haven largely abandoned. Nowadays, the definition of resectability includes a complete resection with tumor-free surgical margins (R0 resection), sparing at least two liver segments having an independent inflow outflow, and biliary drainage. The amount of the liver remnant after resection should not be less than 20 % and 30 % of the total liver volume in normal and cirrhotic patients, respectively [22, 23]. Historically, only 5–10 % of patients with colorectal liver metastases were resectable. Currently, with the advances in diagnostic methods and new therapies, resectability rates have increased [24]. Apart from conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Preserving at least 20 % of future liver remnant is a major obstacle when performing an extended hepatectomy for extensive liver metastases. In this situation, Portal vein embolization (PVE) can be helpful to induce hypertrophy of the contralateral liver to fulfill the minimal liver volume requirement. Even after preoperative chemotherapy or PVE, some patients cannot become eligible for complete CRLM resection through a single hepatectomy. PVE combined with a two-stage resection may be helpful in such circumstances [25]. However, for patients who cannot undergo liver resection because of extensive liver metastases and
13
inadequate remnant liver volume, RFA can play an important role when combined with liver resection [26]. EGFR is widely expressed in skin and EGFR inhibitors (EGFRIs) are characterized by cutaneous adverse effects. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that is mostly mildto moderate in severity and occurs in 70–80 % of patients treated with cetuximab. The rash is rarely dose- or treatment-limiting, and may diminish in intensity with continued exposure to cetuximab. Improvement may be seen after treatment with topical antibiotic preparations, topical steroids or topical retinoids. The rash is self-limiting and resolves fully after discontinuation of cetuximab treatment [27–29]. Data suggest that skin rash may serve as a surrogate marker of EGFR-targeted mAb efficacy. In several analyses, both the presence and intensity of skin toxicity predicted objective tumour response in patients treated with cetuximab or panitumumab in mCRC. In patients receiving cetuximab monotherapy for refractory mCRC, longer survival times were observed in patients with rash of any grade as compared with patients experiencing no rash (p=0.02) [16]. In the OPUS study, a correlation between response rate and skin toxicity was observed: 13 % of patients with no skin toxicity responded versus 42.2 % if G1, 53.2 % if G2, and 66.7 % if G3-4. In the phase III randomised Crystal Study, a slight benefit in terms of overall response rate and progression free survival Cetuximab was achieved in the combination arm; however, greater the skin toxicity higher the progression free survival [16, 17]. In the EPIC study and EVEREST study showed similar results. A correlation between grade of skin toxicity and outcome was reported. Better response rate, progression free survival and survival were achieved in the Cetuximab arm compared to classic schedule [30, 31]. These observations support the consensus that patients with mCRC receiving EGFRIs who develop skin rash should be treated for the rash while continuing EGFR-targeted mAbs, because these patients may derive the greatest clinical benefit from therapy.
Study The aim of our prospective study was to determinethe response rate and resection rate of patients with unresectable colorectal liver metastases following neoadjuvant chemotherapy with cetuximab. Assessment of extent of liver involvement and Functional liver volume reserve (FLVR) was performed by use of spiral computed tomography (CT), which had to be performed within 1 month of the beginning of treatment.
14
Eligibility Criteria Inclusion Criteria
Indian J Surg Oncol (March 2016) 7(1):11–17
Allocation to FOLFOX6 or FOLFIRI was based on medical oncologist preference because both regimen were considered equally effective as first line treatment of colorectal cancer. Subjective symptoms, physical examination results, performance status and all adverse reactions were recorded before each treatment cycle. Treatment courses were repeated every 2 weeks for a total of six courses unless there was evidence of progressive disease.
Patients were eligible for this prospective study if they had histologically confirmed adenocarcinoma of the colon or rectum, with metastatic liver disease unsuitable for resection as defined by a multidisciplinary team including surgical oncologists, radiologists and medical oncologists. Unresectability was defined as not able to achieve at least 30 % of Functional liver volume reserve (FLVR) as defined by CT volumetric analysis or not able to achieve R0 resection (minimum of 1 cm margin) due to close proximity to vessels. In addition, eligible patients were required to have the following characteristics: age 19 to 80 years; an Eastern Co-operative Oncology Group (ECOG) performance status
ORIGINAL ARTICLE
Assessment of Tumor Response and Resection Rates in Unresectable Colorectal Liver Metastases Following Neoadjuvant Chemotherapy with Cetuximab S. P. Somashekhar 1 & K. R. Ashwin 2 & Shabber S. Zaveri 3 & Amit Rauthan 4 & Poonam Patil 4
Received: 26 April 2015 / Accepted: 23 June 2015 / Published online: 5 July 2015 # Indian Association of Surgical Oncology 2015
Abstract To investigate efficacy and safety of cetuximab combined with neo adjuvant chemotherapy regimen in patients with unresectable colorectal liver. This was a prospective trial with rate of Ro liver metastases resection as primary end point. Between January 2010 and December 2014, 46 patients with unresectable liver metastases from colon or rectum were enrolled. Patients received Cetuximab along with neoadjuvant chemotherapy where 34 (74 %) and 12 (26 %) patients received FOLFOX and FOLFIRI, respectively. They were assessed for response after 2–3 cycles by CT scan. Patients with resectable disease were offered liver surgery within 3–6 weeks of the last treatment cycle. The primary end point was resection rate of liver metastases, which was evaluated in all patients. Secondary end points were response rate according to Response evaluation criteria in solid tumors
* S. P. Somashekhar [email protected] K. R. Ashwin [email protected]; [email protected] Shabber S. Zaveri [email protected] Amit Rauthan [email protected] Poonam Patil [email protected] 1
Manipal Comprehensive Cancer Center, Business Advisory Board of MHEPL Manipal Hospital, Bangalore 560017, India
2
Manipal Comprehensive Cancer Centre, No 8, second Anjaneya temple street Seshadripurum, Bangalore 560020, India
3
Department of Surgical Oncology, Manipal Comprehensive Cancer Centre, #98 HAL airport road, Bangalore 560017, India
4
Department of Medical Oncology, Manipal Comprehensive Cancer Centre, #98 HAL airport road, Bangalore 560017, India
(RECIST) criteria, perioperative morbidity and mortality. An objective response was observed in 28 (60.9 %) patients. Seven (15.2 %) patients were reported radiologically to have a complete response (CR); 21 (45.7 %) patients had radiological partial response (PR). An additional 12 patients (26.1 %) demonstrated stable disease (SD) and only six patients (13.0 %) had disease progression (PD). Microscopically complete resections (R0 resection) was performed in all 28 patients (60.9 %). The most frequent toxicities were skin rash and diarrhoea. There was no operative mortality. Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. Complete resection of previously unresectable colorectal liver metastases can be performed with minimal morbidity and mortality. This therapeutic strategy involves a multimodal approach. Keywords Cetuximab . mCRR . Indian study . Liver metastases . Colorectal
Introduction Colorectal carcinoma is one of the most common causes of cancer-related mortalities in both India and the world. Almost half the patients with colorectal cancer will eventually develop liver metastases during the natural course of the disease [1]. The liver is a frequent site of colorectal metastases, and 15 to 25 % of patients have liver metastases at diagnosis. In addition, 50 to 60 % of patients with localized disease at diagnosis eventually develop metastatic disease [2]. Historically, the median survival of patients with metastatic colorectal cancer treated with palliative care is approximately 6 to 12 months [3]. Surgical management of hepatic metastases of colorectal cancer has now become standard of treatment. But only a
12
minority of patients (10–15 %) are considered candidates for resection with overall 5-year survival rates ranging between 25 and 40 %. Therefore, most colorectal hepatic metastases (an estimated 70–80 %) on presentation are unresectable [4, 5]. It was first reported in 1996 by Bismuth et al. that preoperative chemotherapy, using oxaliplatin plus 5- fluorouracil (5-FU) and leucovorin [LV], enabled initially unresectable colorectal liver metastasis (CRLM) patients to gain the chance of undergoing liver resection with an improved 5-year OS of 40 % [6]. Neo adjuvant chemotherapy is currently accepted as the way forward for improving survival in patients with initially unresectable CRLM. Standard combination chemotherapy regimens comprising 5- fluorouracil (5-FU) plus leucovorin [LV] in combination with irinotecan, typically FOLFIRI or oxaliplatin (FOLFOX) have been reported to facilitate the resection of 9–40 % of initially unresectable metastases, and a median survival of 15 to 20 months [7–9]. Although, intensified chemotherapy such as FOLFOXIRI (i.e., oxaliplatin, 5-FU/LV and irinotecan) has been shown to have high response and conversion rates (19 %); however, it has not been generally recommended thus far due to its considerable toxicity [10]. For patients with disease progression during preoperative chemotherapy predicts poor prognosis, for which a change to other alternative chemotherapy regimens is recommended [11]. New data emerging from randomized trials suggest that the addition of targeted agents and a third cytotoxic might be even more effective. The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab is effective when used in combination with chemotherapy. It has a clear indication in second- and third-line treatment of metastatic colorectal cancer. It was recently investigated both as monotherapy and in combination with chemotherapy in the first-line setting. The addition of cetuximab to doublet chemotherapy regimens such as FOLFIRI or FOLFOX has been shown to increase response rates (RR), and prolong progression-free survival (PFS) and overall survival (OS) times in the first-line treatment of patients with CRLM and KRAS wild-type tumours. In these trials, the resectability rate for liver metastases was improved by the addition of cetuximab to chemotherapy, when retrospectively evaluated [12, 13]. More patients with CRLM would be rendered resectable with effective preoperative therapy, as the addition of cetuximab to chemotherapy is feasible in first-line therapy, which has been confirmed in a randomized phase II multicentre study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in the neo-adjuvant treatment of nonresectable colorectal liver metastases confined to the liver (the CELIM study), response rates of 85
Indian J Surg Oncol (March 2016) 7(1):11–17
and 66 % were reported in the FOLFOX6 and FOLFIRI arms, respectively [14]. It is concluded that cetuximab when combined with firstline chemotherapy increases the possibility of resection for patients with initially unresectable liver without increasing surgical mortality or liver injury [15]. The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved PFS compared with chemotherapy alone. They confirmed the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC [16, 17]. Cetuximab combined with triple cytotoxic drug therapy is evaluated, for potential extra efficacy on response rates and clinical outcome. Definitive results from the preoperative chemotherapy for hepatic resection (POCHER) study revealed an RR of 79 % and a complete resection rate of 63 % achieved by FOLFOXIRI plus cetuximab [18]. KRAS encodes a small G protein that links liganddependent receptor activation to intracellular pathways of the EGFR signalling cascade. Mutation at key sites within the gene, commonly at codons 12 and 13, causes constitutive activation of KRAS-associated signalling. Evidence indicates that tumour KRAS mutation is associated with the inefficacy of cetuximab [19]. A recent meta-analysis based on the CRYSTAL and OPUS trials reported the updated clinical efficacy of cetuximab combination therapy according to KRAS and BRAF mutation status. This analysis confirmed that in KRAS wild-type patients, the addition of cetuximab in first-line treatment achieves a statistically significant improvement in response rates, progression free survival, and overall survival compared with chemotherapy alone. However, it also concluded that BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab. BRAF is more likely to be a prognostic factor as the clinical outcome in BRAF mutant patients is worse than those with BRAF wildtype tumours in terms of RR, PFS and OS. Thus, BRAF testing is probably not essential when deciding whether cetuximab should be used [20]. The evaluation of tumour response to treatment is critical for managing patients with advanced cancer. Tumour response, partial and complete response, is the most common criterion used to evaluate the effect of treatment. Imaging and, in particular computed tomography (CT) scan is used to monitor chemotherapy according to the new guidelines for response evaluation (RECIST criteria) [21]. Complete response is usually defined as the disappearance of target lesions on imaging and is considered as a good indicator to evaluate the efficacy of chemotherapy. A potential drawback of neoadjuvant chemotherapy in metastatic colorectal cancer patients is missing the optimal timing of liver resection because of
Indian J Surg Oncol (March 2016) 7(1):11–17
complete response of liver tumours during chemotherapy. Studies show that there is a discrepancy between a complete response being seen on imaging and the complete clearance of cancer. Macroscopic residual disease was found during surgical exploration at the site of liver metastases that were considered to have disappeared on imaging. In addition, in patients with no obvious disease at surgery, microscopic cancer was observed in the resected specimen. Therefore, although complete response seen on imaging may be a useful criterion for evaluating the efficacy of chemotherapy, it does not mean the cure of cancer in most cases [22]. The technical problems for the surgeon are to identify the precise site of the liver needed to be resected and to achieve sufficient resection margin, since he cannot see or palpate any tumour or visualize it using intraoperative ultrasound. To avoid such an intractable condition, it is recommended that the evaluation of liver lesions be repeated every 2 months during preoperative chemotherapy and medical oncologists should refer patients to surgeons as soon as liver metastases are resectable before they have completely disappeared. Despite advances in survival with chemotherapy, surgical resection of hepatic metastases is still considered the only curative option for patients with liver metastases. Liver resection should be reconsidered if the tumour shows response after chemotherapy. The current criteria focus on what should be left after hepatic resection. Previous criteria for resection, such as the size, location, number of intrahepatic metastases and the presence of bilobar or extra hepatic disease haven largely abandoned. Nowadays, the definition of resectability includes a complete resection with tumor-free surgical margins (R0 resection), sparing at least two liver segments having an independent inflow outflow, and biliary drainage. The amount of the liver remnant after resection should not be less than 20 % and 30 % of the total liver volume in normal and cirrhotic patients, respectively [22, 23]. Historically, only 5–10 % of patients with colorectal liver metastases were resectable. Currently, with the advances in diagnostic methods and new therapies, resectability rates have increased [24]. Apart from conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Preserving at least 20 % of future liver remnant is a major obstacle when performing an extended hepatectomy for extensive liver metastases. In this situation, Portal vein embolization (PVE) can be helpful to induce hypertrophy of the contralateral liver to fulfill the minimal liver volume requirement. Even after preoperative chemotherapy or PVE, some patients cannot become eligible for complete CRLM resection through a single hepatectomy. PVE combined with a two-stage resection may be helpful in such circumstances [25]. However, for patients who cannot undergo liver resection because of extensive liver metastases and
13
inadequate remnant liver volume, RFA can play an important role when combined with liver resection [26]. EGFR is widely expressed in skin and EGFR inhibitors (EGFRIs) are characterized by cutaneous adverse effects. The most commonly reported adverse event associated with cetuximab treatment is an acneiform rash that is mostly mildto moderate in severity and occurs in 70–80 % of patients treated with cetuximab. The rash is rarely dose- or treatment-limiting, and may diminish in intensity with continued exposure to cetuximab. Improvement may be seen after treatment with topical antibiotic preparations, topical steroids or topical retinoids. The rash is self-limiting and resolves fully after discontinuation of cetuximab treatment [27–29]. Data suggest that skin rash may serve as a surrogate marker of EGFR-targeted mAb efficacy. In several analyses, both the presence and intensity of skin toxicity predicted objective tumour response in patients treated with cetuximab or panitumumab in mCRC. In patients receiving cetuximab monotherapy for refractory mCRC, longer survival times were observed in patients with rash of any grade as compared with patients experiencing no rash (p=0.02) [16]. In the OPUS study, a correlation between response rate and skin toxicity was observed: 13 % of patients with no skin toxicity responded versus 42.2 % if G1, 53.2 % if G2, and 66.7 % if G3-4. In the phase III randomised Crystal Study, a slight benefit in terms of overall response rate and progression free survival Cetuximab was achieved in the combination arm; however, greater the skin toxicity higher the progression free survival [16, 17]. In the EPIC study and EVEREST study showed similar results. A correlation between grade of skin toxicity and outcome was reported. Better response rate, progression free survival and survival were achieved in the Cetuximab arm compared to classic schedule [30, 31]. These observations support the consensus that patients with mCRC receiving EGFRIs who develop skin rash should be treated for the rash while continuing EGFR-targeted mAbs, because these patients may derive the greatest clinical benefit from therapy.
Study The aim of our prospective study was to determinethe response rate and resection rate of patients with unresectable colorectal liver metastases following neoadjuvant chemotherapy with cetuximab. Assessment of extent of liver involvement and Functional liver volume reserve (FLVR) was performed by use of spiral computed tomography (CT), which had to be performed within 1 month of the beginning of treatment.
14
Eligibility Criteria Inclusion Criteria
Indian J Surg Oncol (March 2016) 7(1):11–17
Allocation to FOLFOX6 or FOLFIRI was based on medical oncologist preference because both regimen were considered equally effective as first line treatment of colorectal cancer. Subjective symptoms, physical examination results, performance status and all adverse reactions were recorded before each treatment cycle. Treatment courses were repeated every 2 weeks for a total of six courses unless there was evidence of progressive disease.
Patients were eligible for this prospective study if they had histologically confirmed adenocarcinoma of the colon or rectum, with metastatic liver disease unsuitable for resection as defined by a multidisciplinary team including surgical oncologists, radiologists and medical oncologists. Unresectability was defined as not able to achieve at least 30 % of Functional liver volume reserve (FLVR) as defined by CT volumetric analysis or not able to achieve R0 resection (minimum of 1 cm margin) due to close proximity to vessels. In addition, eligible patients were required to have the following characteristics: age 19 to 80 years; an Eastern Co-operative Oncology Group (ECOG) performance status
